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Other nonneoplastic conditions

Acute lung injury

ARDS / DAD

Authors: Akira Yoshikawa, M.D., Andrey Bychkov, M.D., Ph.D.

Editorial Board Member: Jefree J. Schulte, M.D.

Last author update: 26 August 2022

Last staff update: 29 November 2022

Copyright: 2003-2023, PathologyOutlines.com, Inc.

PubMed search: (Acute respiratory distress syndrome) ARDS (Diffuse alveolar damage) DAD

See also: Acute fibrinous and organizing pneumonia

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Table of Contents

Cite this page: Yoshikawa A, Bychkov A. ARDS / DAD. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lungnontumordiffusealveolardamage.html. Accessed February 3rd, 2023.

Definition / general

In 1994, the American European Consensus Conference (AECC) defined acute respiratory distress syndrome (ARDS) as the acute onset of hypoxemia with bilateral infiltrates on frontal chest radiograph, with no evidence of left atrial hypertension (Am J Respir Crit Care Med 1994;149:818)
In 2012, the ARDS Task Force revised the new definition (see Diagnosis) (JAMA 2012;307:2526)
Diffuse alveolar damage (DAD) is manifested by injury to alveolar lining and endothelial cells, pulmonary edema, hyaline membrane formation and later by proliferative changes involving alveolar and bronchiolar lining cells and interstitial cells (Am J Pathol 1976;85:209)

Essential features

Acute and rapidly progressive hypoxia with bilateral pulmonary edema due to alveolar injury caused by pulmonary or systemic insults
40% die within 28 days from onset of ARDS, mainly due to infection / sepsis and multiple organ dysfunction syndrome
Although DAD is the typical morphology of ARDS, clinical syndrome of ARDS is not synonymous with the pathologic diagnosis of DAD
DAD pattern is often characterized by hyaline membranes in acute phase but shows a wide variety of findings that makes the diagnosis challenging

Terminology

Previously known as adult respiratory distress syndrome
Acute lung injury, an overlapping entity suggested in AECC definition, was removed from Berlin definition; the AECC definition of acute lung injury non-ARDS is compatible with Berlin definition of mild ARDS (JAMA 2012;307:2526)

ICD coding

ICD-10: J80 - acute respiratory distress syndrome

Epidemiology

Mean age: 60 years old; from children to elderly
M:F = 3:2
Incidence of 10.6 - 78.9 per 100,000 person years (N Engl J Med 2005;353:1685, Intensive Care Med 2009;35:1352)
Incidence of ARDS in intensive care unit (ICU) (JAMA 2016;315:788):
- 10.4% of all ICU patients
- 67.2% of patients with acute hypoxemic respiratory failure
- ARDS is frequently undiagnosed (60.2% recognized by clinician) or late diagnosed (34.0% recognized at the time of criteria fulfillment)

Sites

Diffusely involves bilateral lobes of the lung without upper or lower lobe predominance
Distribution can be regional, depending on the degree and cause of the inflammation

Pathophysiology

Pathogenesis (N Engl J Med 2000;342:1334, Lancet 2016;388:2416)
- Exudative (acute) phase: 1 - 7 days
  - Neutrophil mediated inflammation destroys the alveolar capillary barrier (alveolar epithelium and endothelium), increases its permeability and causes intra-alveolar hemorrhage and edema
  - Protein rich edema interacts with alveolar surfactants, resulting in decreased pulmonary compliance
  - Hyaline membranes develop on alveolar wall where epithelium is denudated and disrupted
- Proliferative / organizing (subacute) phase: 1 - 3 weeks
  - Proliferation of type II pneumocytes and subsequent differentiation into type I pneumocytes
  - Proliferation of myofibroblasts
  - Drainage of alveolar edema by restored type II pneumocytes
- Fibrotic (chronic) phase: after 3 weeks
  - Collagenous fibrosis in alveolar spaces and interstitium
  - Refractory rigidity of alveoli due to architectural remodeling
Pathophysiology of hypoxia
- Collapse of alveoli
- Increased right to left intrapulmonary shunt
- Decreased pulmonary compliance
  - Surfactant malfunction
  - Fibrosis
- Decreased diffusing capacity due to pulmonary edema
- Increased ventilation perfusion mismatch
- Increased pulmonary vascular resistance
Mechanism of ARDS to cause multiple organ dysfunction syndrome is not clear
- Ventilator induced lung injury may play a critical role for upregulation of cytokines and eventual development of multiple organ dysfunction syndrome (Curr Opin Crit Care 2011;17:1, Respir Care 2014;59:1422)

Etiology

Pulmonary and extrapulmonary origin (N Engl J Med 2000;342:1334)

Direct lung injury	Indirect lung injury
Common causes Infectious pneumonia Aspiration of gastric contents	Common causes Sepsis Severe trauma or burn, especially with shock and multiple transfusions
Less common causes Pulmonary contusion Fat emboli Near drowning Inhalational injury (particle, gas) Reperfusion pulmonary edema after lung transplantation or pulmonary embolectomy	Less common causes Cardiopulmonary bypass Drug Acute pancreatitis Autoimmune disease Transfusion related acute lung injury

Infection
- Bacterial: mycoplasma, mycobacteria, legionella, rickettsia
- Viral: influenza virus, herpes virus, cytomegalovirus, hantavirus, SARS-CoV-2 (coronavirus disease 2019, COVID-19) (Histopathology 2020;77:570)
- Fungal: Pneumocystis jirovecii
Drug (N Engl J Med 2000;342:1334)
- Chemotherapeutic drugs: methotrexate, bleomycin, azathioprine, busulfan
- Molecular targeted drugs
- Gold based
- Amiodarone
- Penicillamine
- Nitrofurantoin
Autoimmune disease
- Polymyositis / dermatomyositis
  - Especially in clinically amyopathic dermatomyositis
- Systemic lupus erythematosus
- Scleroderma
- Rheumatoid arthritis
- Polyarteritis nodosa
- Undifferentiated (subclinical) connective tissue disease
  - Often positive for serum anti-MDA-5 antibody or anti-ARS antibody (Medicine (Baltimore) 2012;91:220, BMJ Case Rep 2016;2016:bcr2016217624, Tuberc Respir Dis (Seoul) 2016;79:188)
Inhalation
- Smoke
- Sulfur dioxide
- Oxygen
- Nitrogen dioxide

Diagrams / tables

Images hosted on other servers:

Acute phase

Organizing phase

Clinical features

Acute and progressive respiratory failure
- Usually starts 12 - 48 hours after the initial insult
- Shortness of breath; dyspnea on exertion followed by dyspnea at rest
- Hypoxia; PaO₂ / FiO₂ ≤ 300 mm Hg
Often followed by sepsis and multiple organ dysfunction syndrome (JAMA 2016;315:788)
Respiratory dysfunction and physical disability may persist for months after remission of ARDS, with gradual improvement (N Engl J Med 2003;348:683)

Diagnosis

Diagnosis of ARDS is based on clinical manifestation and its severity is evaluated with ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO₂ / FiO₂)
Berlin definition (JAMA 2012;307:2526)
- Timing
  - Within 1 week of a known clinical insult or new or worsening respiratory symptoms
- Chest imaging
  - Assessed by chest Xray or CT
  - Bilateral opacities; not fully explained by effusions, lobar / lung collapse or nodules
- Origin of edema
  - Respiratory failure not fully explained by cardiac failure or fluid overload
  - Need objective assessment (e.g. echocardiography) to exclude hydrostatic edema if no risk factor present
- Oxygenation (with positive end expiratory pressure [PEEP] or continuous positive airway pressure [CPAP] ≥ 5 cm H₂O)
  - Mild: 200 < PaO₂ / FiO₂ ≤ 300 mm Hg
  - Moderate: 100 < PaO₂ / FIO₂ ≤ 200 mm Hg
  - Severe: PaO₂ / FiO₂ ≤ 100 mm Hg
Not all ARDS show DAD pattern
- ARDS can present with organizing DAD and acute fibrinous organizing pneumonia as well
- DAD can be seen as a nonspecific manifestation of the agonal phase and shock
Although rarely performed, lung biopsy can be helpful for critical care and prognosis estimation in patients with ARDS
- Open lung biopsy provided a specific diagnosis for 56 - 84% of ARDS patients and an alternative treatment for 73% of cases (Ann Thorac Surg 2014;98:1254, Crit Care 2015;19:228, Intensive Care Med 2015;41:222)
- ARDS with DAD is related to worse prognosis (see Prognostic factors)
- Carefully consider biopsy if there is a high prediction for beneficial result and the risk of empirical therapy is not suitable or unsuccessful (Chest 2015;148:1073)

Laboratory

Arterial blood gas test
- Hypoxemia
- Ratio of pulse oximetric oxygen saturation to FIO2 (SpO₂ / FiO₂) may be helpful for instant follow up (Chest 2007;132:410)
  - SpO₂ / FiO₂ of 235 ≈ PaO₂ / FiO₂ of 200 (sensitivity: 85%, specificity: 85%)
  - SpO₂ / FiO₂ of 315 ≈ PaO₂ / FiO₂ of 300 (sensitivity: 91%, specificity: 56%)
Other blood tests
- Increased C reactive protein
- Increased procalcitonin in septic ARDS
- Increased ferritin (Am J Respir Crit Care Med 1999;159:1506)
- Increased KL-6
- Brain natriuretic peptide (BNP) test may helpful to distinguish ARDS and cardiogenic pulmonary edema (Chest 2007;131:964)
  - BNP ≤ 200 pg/mL is suggestive for ARDS (sensitivity: 40%, specificity: 91%)
  - BNP ≥ 1,200 pg/mL is suggestive for cardiogenic pulmonary edema (sensitivity: 52%, specificity: 92%)

Radiology description

General
- Heterogeneous bilateral shadows due to pulmonary edema
- Rule out atelectasis, pleural effusion and mass
- Takes 12 - 24 hours from onset to be apparent
Chest Xray
- Exudative phase: ground glass opacity and consolidation with air bronchogram
- Proliferative / organizing and fibrotic phases: reticular shadow and volume reduction
Chest CT (Radiology 1999;211:859)
- Exudative phase
  - Patchy to diffuse ground glass opacity, with or without interlobular septal thickening
  - Dorsal consolidation due to infiltrate
- Proliferative / organizing phase
  - Ground glass opacity with bronchiolectasis and bronchiectasis
  - Volume reduction
- Fibrotic phase
  - Septal thickening and reticular shadow in ground glass opacity
  - Peripheral cystic and honeycomb-like lesions due to fibrosis

Radiology images

Images hosted on other servers:

Changes in ARDS

Exudative phase

Proliferative / organizing phase

Fibrotic phase

ARDS on CT

Prognostic factors

Septic shock and multiple organ dysfunction syndrome account for about 50% of deaths in patients with ARDS, while respiratory failure is responsible for 10 - 20% of deaths (Am J Respir Crit Care Med 2013;187:761, Chest 2005;128:525, Chest 1989;96:885, Clin Chest Med 2006;27:725)
- First 7 - 10 days are the most relevant for the prognosis of ARDS (JAMA 2016;315:788)
- Of all ARDS patients, 93.1% developed ARDS in the first 48 hours
Mortality rate at day 28 and at hospital discharge was 29.6% and 34.9% for mild ARDS, 35.2% and 40.3% for moderate and 40.9% and 46.1% for severe, respectively
Mortality is higher for ARDS with DAD (71.9%) than ARDS without DAD (45.5%) (Crit Care 2015;19:228, PLoS One 2017;12:e0180018, Chest 2016;149:1155)
Prognosis of ARDS patients improved over the last decades (Chest 2008;133:1120)

Case reports

31 year old man with ARDS / DAD and eosinophilic pneumonia due to amphetamine smoking (Chin J Physiol 2014;57:295)
41 year old woman died of ARDS / DAD due to influenza A virus infection (Jpn J Infect Dis 2010;63:72)
43 year old man died of ARDS due to clinically amyopathic dermatomyositis (Case Rep Crit Care 2016;2016:7379829)
45 year old woman died of ARDS / DAD due to rabies (Kaohsiung J Med Sci 2006;22:94)
49 year old man died of ARDS / DAD due to EBV positive diffuse large B cell lymphoma (Int J Clin Exp Pathol 2014;7:1742)
72 year old woman died of ARDS / DAD due to scrub typhus (J Korean Med Sci 2000;15:343)
72 year old man died of ARDS / DAD due to influenza B virus infection (Respirol Case Rep 2015;3:61)
75 year old man died of ARDS / DAD due to gemcitabine chemotoxicity (Intern Med 2003;42:1022)
77 year old woman died of ARDS / DAD due to acute interstitial pneumonia (Case Rep Med 2011;2011:628743)
93 year old woman with segmented DAD due to COVID-19 (Pathol Int 2020;70:820)

Treatment

Removal of the original insult
Oxygen therapy for respiratory failure (Lancet 2016;388:2416)
- Mechanical ventilation
  - PEEP or CPAP ≥ 5 cm H₂O
  - With or without neuromuscular blockade, prone position and extracorporeal membrane oxygenation
Other supportive care
- Fluid management
- Pharmacotherapy
  - Glucocorticoid
  - Anticoagulant
Since no treatment drastically improves the respiratory failure of ARDS, respiratory and systemic supportive care is needed until the patient survives from ARDS

Gross description

Brown to gray consolidative lesion with indistinct borders, diffusely involving bilateral lobes
Elastic hard and greasy due to transudate within alveolar spaces and interstitial edema
Heavy and shrunken due to fibrosis and collapse of the tissue
Dots of hemorrhage on pleural surface

Gross images

Contributed by Yale Rosen, M.D.

Diffuse alveolar damage (DAD)

Patchy lung involvement

Diffuse alveolar damage (DAD)

Microscopic (histologic) description

Histopathology of DAD progresses from exudative (acute) phase through proliferative / organizing (subacute) phase to chronic fibrotic phase roughly corresponding to the period of ARDS (Am J Pathol 1976;85:209, Arch Pathol Lab Med 2010;134:719, Clin Chest Med 2000;21:435, N Engl J Med 2000;342:1334)
- Phase of the disease is almost synchronous throughout the lung
- Features of different phases may be combined in the transitional period or with repeated bouts of lung injury
Exudative (acute) phase
- Alveolar change
  - Hyaline membranes on alveolar duct or sacs
  - Interstitial and intra-alveolar edema
  - Collapsed alveoli
- Epithelial change
  - Denudation and necrosis of type I pneumocytes
- Vascular change
  - Necrosis of endothelial cells
  - Neutrophil aggregation
  - Microthromboemboli
  - Hemorrhage
Proliferative / organizing (subacute) phase
- Alveolar change
  - Remnants of hyaline membrane with or without organization
  - Interstitial and intra-alveolar proliferation of myofibroblasts
  - Lymphocytic infiltration
- Epithelial change
  - Proliferation / hyperplasia of type II pneumocytes
- Vascular change
  - Endothelial injury and thromboemboli in arterioles
Fibrosis phase
- Alveolar change
  - Collagenous fibrosis
  - Microscopic honeycomb-like change
  - Traction bronchiolectasis
- Epithelial change
  - Squamous metaplasia / hyperplasia
- Vascular change
  - Remodeling of arteries
  - Intimal fibrosis
  - Thickening of media
Others
- May have superimposed pneumonia
- Fibrin deposition
- DAD with prominent organizing pneumonia is also called organizing DAD

Microscopic (histologic) images

Contributed by Akira Yoshikawa, M.D. and Yale Rosen, M.D.

Hyaline membrane

Hyaline membranes and fibrin

Masson body

Organizing DAD

Collagenous fibrosis

Fibroblastic proliferation

Interstitial organization

Inflammatory cells

Virtual slides

Images hosted on other servers:

Exudative phase

Cytology description

Bronchoalveolar lavage (BAL) fluid
- Increased neutrophils in ARDS
- Can be helpful for the diagnosis of underlying disease

Positive stains

Fiber staining (e.g. elastica van Gieson) is helpful to evaluate fibrosis and to evaluate the destruction of the alveolar architecture
Giemsa, Grocott and Ziehl-Neelsen stains are helpful to identify pathogens
Immunohistochemistry (not of practical utility):
- Cytokeratin highlights collapsed alveoli and lung architecture

Electron microscopy description

Changes in epithelium, endothelium and interstitium (N Engl J Med 2000;342:1334)
- Exudative phase
  - Vacuolization in damaged endothelial cells
  - Replacement of epithelial cells by hyaline membrane on the basement membrane
- Proliferative / organizing and fibrotic phases
  - Reepithelialization of type II pneumocytes with microvilli and lamellar bodies with surfactant
  - Flattening of cytoplasm and loss of lamellar bodies and microvilli of type II pneumocyte, indicating transformation to type I pneumocyte
  - Collagen deposition

Videos

Histology of DAD

Sample pathology report

Lung, autopsy:
- Diffuse alveolar damage (see comment)
- Comment: Histologic sections reveal diffuse alveolar damage in subacute and chronic phases involving bilateral lobes; the former is represented by fibrin deposition, organizing pneumonia and focal hyaline membranes and the latter by interstitial fibrosis, fibroblastic foci and the destruction of alveolar architecture. Acute bacterial pneumonia is also superimposed.

Differential diagnosis

Major entities:
- Acute exacerbation of usual interstitial pneumonia / idiopathic pulmonary fibrosis (UIP / IPF):
  - Acute exacerbation of IPF and DAD are clinically and morphologically similar
  - IPF shows chronic and dense collagen fibrosis with smooth muscle hyperplasia, while fibrosis in DAD is not so dense and usually lacks smooth muscle hyperplasia
- Acute interstitial pneumonia:
  - So called Hamman-Rich syndrome or idiopathic DAD
  - Lack of clinical criteria of ARDS
- Cardiogenic pulmonary edema:
  - BNP ≥ 1,200 pg/mL
  - Congestive heart failure on echocardiograph
  - Right heart catheterization is now not recommended due to negative influence to prognosis
- Drug induced lung injury:
  - History of causative drug
  - Remission of symptoms after withdrawal of the responsible drug
Minor entities:
- Organizing pneumonia:
  - Migratory sign on imaging
  - Good response to corticosteroid
- Eosinophilic pneumonitis:
  - Current smoker or history of particle inhalation
  - Eosinophilia (> 25%) in bronchoalveolar lavage
  - Good response to corticosteroid
- Hypersensitivity pneumonitis:
  - History of antigen exposure
  - Remission of symptoms after removal of the causative antigen
  - Lymphocytosis (> 30%) in bronchoalveolar lavage
  - Diffuse centrilobular nodular shadow with ground glass opacity, usually in upper lobes
- Miliary tuberculosis:
  - Diffuse nodular shadow (≤ 3 mm) involving whole lobes
  - Mycobacterium tuberculosis in bronchoalveolar lavage or biopsy specimen
- Lymphangitic carcinomatosis:
  - Known malignancy
  - Tumor cells in bronchoalveolar lavage or biopsy specimen

Additional references

J Clin Pathol 2009;62:387, Clin Med Insights Circ Respir Pulm Med 2016;9:123, Arch Pathol Lab Med 2017;141:916, Leslie: Practical Pulmonary Pathology: A Diagnostic Approach, 2nd Edition, 2011, Cagle: Lung and Pleural Pathology, 1st Edition, 2015

Board review style question #1

Which phase of diffuse alveolar damage (DAD) is most clearly demonstrated in this histological image?

Active
Exudative (acute)
Fibrotic (chronic)
Postinflammatory
Proliferative / organizing (subacute)

Board review style answer #1

E. Proliferative / organizing (subacute). Masson body, polypoid proliferation of spindle shaped fibroblasts, is noted in the alveoli.

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Reference: ARDS / DAD

Board review style question #2

Which of the following findings is most suggestive of acute respiratory distress syndrome (ARDS) / diffuse alveolar damage (DAD)?

Bacterial pneumonia
Diffuse collagenous fibrosis
Hyaline membranes
Organizing pneumonia
Proliferation of atypical pneumocytes

Board review style answer #2

C. Hyaline membranes. Hyaline membranes morphologically represent the damage of pneumocytes and endothelium in DAD.

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Reference: ARDS / DAD

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